Biology subjects

Raj, K.

Publications and source records attributed to Raj, K..

27 records · Page 2Linked to original sources

bioRxiv2020

Epigenetic clock and methylation studies in cats

Human DNA methylation profiles have been used successfully to develop highly accurate biomarkers of aging ("epigenetic clocks"). Although these human epigenetic clocks are not immediately applicable to all species of the animal kingdom, the principles underpinning them appear to be conserved even in animals that are evolutionarily far removed from humans. This is exemplified by recent development of epigenetic clocks for mice and other mammalian species. Here, we describe epigenetic clocks for the domestic cat (Felis catus), based on methylation profiles of CpGs with flanking DNA sequences that are highly conserved between multiple mammalian species. Methylation levels of these CpGs are measured using a custom-designed Infinium array (HorvathMammalMethylChip40). From these, we present 3 epigenetic clocks for cats; of which, one applies only to blood samples from cats, while the remaining two dual-species human-cat clocks apply both to cats and humans. As the rate of human epigenetic ageing is associated with a host of health conditions and pathologies, it is expected that these epigenetic clocks for cats would do likewise and possess the potential to be further developed for monitoring feline health as well as being used for identifying and validating anti-aging interventions.

developmental biology↗

bioRxiv2020

Reversing age: dual species measurement of epigenetic age with a single clock

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

developmental biology↗

bioRxiv2020

Interplay of host regulatory network on SARS-CoV-2 binding and replication machinery

We dissect the mechanism of SARS-CoV-2 in human lung host from the initial phase of receptor binding to viral replication machinery. We constructed two independent lung protein interactome to reveal the signaling process on receptor activation and host protein hijacking machinery in the pathogenesis of virus. Further, we test the functional role of the hubs derived from both interactome. Most hubs proteins were differentially regulated on SARS-CoV-2 infection. Also, the proteins of viral replication hubs were related with cardiovascular disease, diabetes and hypertension confirming the vulnerability and severity of infection in the risk individual. Additionally, the hub proteins were closely linked with other viral infection, including MERS and HCoVs which suggest similar infection pattern in SARS-CoV-2. We identified five interconnecting cascades between hubs of both networks that show the preparation of optimal environment in the host for viral replication process upon receptor attachment. Interestingly, we propose that seven potential miRNAs, targeting the intermediate phase that connects receptor and viral replication process a better choice as a drug for SARS-CoV-2.

systems biology↗

bioRxiv2019

Mindfulness meditators show enhanced working memory performance concurrent with different brain region engagement patterns during recall

Mindfulness meditation has been shown to improve working memory (WM). However, the altered brain activity underpinning these improvements is underexplored. In non-meditating individuals, modulation of theta and alpha oscillations and 1/f aperiodic activity during WM has been found to be related to WM performance. Resting theta and alpha oscillations have been found to differ in meditators, but WM related oscillation changes and 1/f aperiodic activity have not yet been examined. Additionally, WM event-related-potentials (ERPs) are modulated by attention, which is also enhanced by meditation, so these neural measures are candidates for exploring neural activity underpinning WM improvement in meditators. We recorded EEG from 29 controls and 29 meditators during a modified Sternberg WM task and compared theta, alpha, and 1/f aperiodic activity during the WM delay, and ERPs time-locked to the WM probe. Meditators responded more accurately (p = 0.008, Cohens d = 0.688). Meditators also showed different ERP distributions with earlier left-temporal activation and more frontal distribution of activity (FDR-p = 0.0186, {eta}2 = 0.0903), as well as a reduction in overall neural response strength (FDR-p = 0.0098, {eta}2 = 0.1251). While a higher proportion of meditators showed theta oscillations during the WM delay, no other differences in theta, alpha or 1/f aperiodic activity were present. These results suggest that increased WM performance in meditators might not be the result of higher amplitudes of typical WM activity, but instead due to an alternative neural strategy during WM decision making, which may allow more accurate responses with less neural activation.\n\nHighlights- Long term mindfulness meditators showed improved working memory (WM) accuracy\n- This was concurrent with earlier left temporal activation following probe stimuli\n- As well as a more frontal distribution and reduced overall neural response strength\n- No oscillation differences were present in the working memory delay period\n- Improved WM from altered neural strategy rather than increased neural activity

neuroscience↗

bioRxiv2019

Phenotypic design choices for enhanced productivity in microbial chemical production processes

Microbial metabolism can be harnessed to produce a broad range of industrially important chemicals. Often, three key process variables: Titer, Rate and Yield (TRY) are the target of metabolic engineering efforts to improve microbial hosts toward industrial production. Previous research into improving the TRY metrics have examined the efficacy of having distinct growth and production stages to achieve enhanced productivity. However, these studies assumed a switch from a maximum growth to a maximum production phenotype. Hence, phenotypes with intermediate growth and chemical production for the growth and production stages of two-stage processes are yet to be explored. The impact of reduced growth rates on substrate uptake adds to the need for intelligent choice of operating points while designing two-stage processes. In this work, we develop a computational framework that scans the phenotypic space of microbial metabolism to identify ideal growth and production phenotypic targets, to achieve optimal TRY targets. Using this framework, with Escherichia coli as a model organism, we compare two-stage processes that use dynamic pathway regulation, with one-stage processes that use static intervention strategies, for different bioprocess objectives. Our results indicate that two-stage processes with intermediate growth during the production stage always result in optimal TRY values even in cases where substrate uptake is limited due to reduced growth during chemical production. By analyzing the flux distributions for the production enhancing strategies, we identify key reactions and reaction subsystems that require perturbation to achieve a production phenotype for a wide range of metabolites in E. coli. Interestingly, flux perturbations that increase phosphoenolpyruvate and NADPH availability are enriched among these production phenotypes. Furthermore, reactions in the pentose phosphate pathway emerge as key control nodes that function together to increase the availability of precursors to most products in E. coli. The inherently modular nature of microbial metabolism results in common reactions and reaction subsystems that need to be regulated to modify microbes from their target of growth to the production of a diverse range of metabolites. Due to the presence of these common patterns in the flux perturbations, we propose the possibility of a universal production strain.Competing Interest StatementThe authors have declared no competing interest.View Full Text

synthetic biology↗

bioRxiv2019

Mindfulness meditation alters neural activity underpinning working memory during tactile distraction

Evidence suggests that mindfulness meditation (MM) improves selective attention and reduces distractibility by enhancing top-down neural modulation. Altered P300 and alpha neural activity from MM have been identified and may reflect the neural changes that underpin these improvements. Given the proposed role of alpha activity in supressing processing of task-irrelevant information, it is theorised that altered alpha activity may underlie increased availability of neural resources in meditators. The present study investigated attentional function in meditators using a cross-modal study design, examining the P300 during working memory (WM) and alpha activity during concurrent distracting tactile stimuli. Thirty-three meditators and 27 healthy controls participated in the study. Meditators showed a more frontal distribution of P300 neural activity following WM stimuli (p = 0.005, {eta}{superscript 2} = 0.060) and more modulation of alpha activity at parietal-occipital regions between single (tactile stimulation only) and dual task demands (tactile stimulation plus WM task) (p < 0.001, {eta}{superscript 2} = 0.065). Additionally, meditators performed more accurately than controls (p = 0.038, {eta}{superscript 2} = 0.067). The altered distribution of neural activity concurrent with improved WM performance suggests greater attentional resources dedicated to task related functions such as WM in meditators. Thus, meditation-related neural changes are likely multi-faceted involving both altered distribution and also amplitudes of brain activity, enhancing attentional processes depending on task requirements.

neuroscience↗

bioRxiv2018

Mindfulness meditators do not show differences in electrophysiological measures of error processing

Mindfulness meditation may improve attention and self-regulation. One component of attention and self-regulation that may allow these improvements is performance monitoring. Neural correlates of performance monitoring can be objectively measured with electroencephalogram (EEG) via the error related negativity (ERN) and error positivity (Pe). Previous research assessing the ERN and Pe in meditators has resulted in inconsistent findings; some have reported alteration in peak amplitudes from both very brief meditation practice and long-term meditation practice, while others have failed to provide evidence for differences in the ERN or Pe. However, recently developed EEG analysis techniques allow for more rigorous analyses than have been used in past investigations. The current study measured the ERN and Pe, as well as post-error alpha suppression, during a Go/Nogo task, and emotional and colour Stroop tasks. The measures were compared between 22 experienced meditators (mean of 8 years of practice) and 20 healthy controls. The results suggested no differences in the ERN, Pe, or post-error alpha suppression (all p > 0.05), even when varying multiple analysis parameters. The study showed equivalent statistical power to previous research, and > 85% power to detect medium effect sizes present in previous research. Bayes Factor analysis indicated the null hypotheses were > 3.5 more likely than any of the alternative hypotheses for the ERN or Pe. These results suggest that meditation may not alter neural activity related to error processing, despite prior research suggesting that it does.

neuroscience↗

bioRxiv2018

Mindfulness meditators show altered distributions of early and late neural activity markers of attention in a response inhibition task

Attention is a vital executive function, since other executive functions are largely dependent on it. Mindfulness meditation has been shown to enhance attention. However, the components of attention altered by meditation and the related neural activities are underexplored. In particular, the contributions of inhibitory processes and sustained attention are not well understood. Additionally, it is not clear whether improvements in attention are related to increases in the strength of typically activated brain areas, or the recruitment of additional or alternative brain areas. To address these points, 34 meditators were compared to 28 age and gender matched controls during electroencephalography (EEG) recordings of neural activity during a Go/Nogo response inhibition task. This task generates a P3 event related potential, which is related to response inhibition processes in Nogo trials, and attention processes across both trial types. Compared with controls, meditators were more accurate at responding to Go and Nogo trials. Meditators showed a more frontally distributed P3 to both Go and Nogo trials, suggesting more frontal involvement in sustained attention rather than activity specific to response inhibition. Unexpectedly, meditators also showed increased positivity over the right parietal cortex prior to visual information reaching the occipital cortex. Both results were positively related to increased accuracy across both groups. The results suggest that meditators have an increased capacity to modulate a range of neural processes in order to meet task requirements, including higher order processes, and sensory anticipation processes. This increased capacity may underlie the improved attentional function observed in mindfulness meditators.

neuroscience↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗